Metastatic or unresectable recurrent medullary thyroid carcinoma (MTC) continues to present a special challenge for the treating oncologist. Chemotherapy alone, particularly using doxorubicin (Adriamycin) has had limited success, while external beam radiation therapy may only be used to control local disease. Our group has recently utilized a third modality, namely, radioimmunotherapy (RAIT) with radiolabeled anti- carcinoembryonic antigen (CEA) monoclonal antibodies (MAbs). Based on the anti-tumor effects observed with RAIT and the reported responses with doxorubicin, we hypothesized that a combined modality approach of RAIT and doxorubicin may be especially attractive for this type of disease. In addition to the additive anti-tumor effects expected by combining both modalities, doxorubicin acts as a radiosensitizing cytotoxic agent, therefore, potentially resulting in synergistic anti-tumor effects. In addition to the additive anti-tumor effects expected by combining both modalities, doxorubicin acts as a radiosensitizing cytotoxic agent, therefore, potentially resulting in synergistic anti-tumor effects. While combining both modalities is expected to result in potentially increased myelotoxicity, this toxicity will be addressed by peripheral blood stem cell rescue (PBSCR) and addition of hematopoietic growth factors such as GCSF. Most importantly, the addition of RAIT is not expected to add substantially to the cardiac toxicity of doxorubicin nor to the mucositis that tends to occur when chemotherapy is combined with external beam radiation. In patients with doxorubicin-resistant MTC, the use of other chemotherapeutic agents (such as carboplatin and taxol) in combination with RAIT will be studied. In this application, we propose to conduct two phase I dose-escalating trials with 90Y-humanized second generation high-affinity anti-CEA MN-14 combined with doxorubicin (Study 1) or other chemotherapy agents (Study 2) to determine the dose-limiting toxicity and maximum tolerated dose of these combinations in patients with MTC. The feasibility of administering multiple cycles of these combinations will also be explored. Finally, the efficacy of this combined modality treatment will be determined in phase II therapy trials. In addition to the clinical studies, preclinical experiments will be performed to develop concepts to be applied for clinical programs. It is expected that this novel multimodal approach will have a significant efficacy in the treatment of metastatic MTC, and thus potentially have a major impact on the management of these patients.